Method of treatment of schizophrenia

ABSTRACT

The invention relates generally to improvements in the treatment of psychotic symptoms, and more particularly, to improvements in the identification of an individual or a population of individuals for whom treatment with iloperidone, an iloperidone metabolite, or pharmaceutically-acceptable salts thereof may provide a particular benefit in treating an individual&#39;s psychotic symptoms based on the individual&#39;s genotype at the PPEF2 locus.

CROSS REFERENCE TO RELATED APPLICATION

This patent application is a continuation of US non-provisional patentapplication Ser. No. 17/070,622, filed Oct. 14, 2020, which claims thebenefit of U.S. provisional patent application Ser. No. 62/915,395,filed Oct. 15, 2019, the contents of which are incorporated herein asthough fully set forth.

BACKGROUND OF THE INVENTION

The invention relates generally to improvements in the treatment ofpsychotic symptoms, and more particularly, identifying individuals or apopulation of individuals for whom treatment may provide a particularbenefit in treating an individual's psychotic symptoms based on theindividual's genotype at the PPEF2 locus.

Schizophrenia is a psychotic disorder affecting between about 0.6% and1.9% of the US population. It is characterized by the presence ofpositive symptoms (e.g., hallucinations and delusions) and negativesymptoms (e.g., blunted affect and social withdrawal), as well asimpairment of cognitive functions (e.g., verbal memory, informationprocessing). The nature and severity of an individual's schizophreniamay be measured using a number of scales, the most widely used being thePositive and Negative Syndrome Scale (PANSS). A number of PANSSsubscales may also be used, such as the PANSS general psychopathologysubscale (PANSS-GP), the PANSS positive symptom subscale (PANSS-P), andthe PANSS negative symptom subscale (PANSS-N). The PANSS total score(PANSS-T) is comprised of all PANSS subscales.

There is much evidence that schizophrenia may not be caused by a singlemajor gene, but rather is a complex genetic disorder with amultifactorial mode of inheritance. Genetic studies have implicated manydifferent genes and pathways, but much of the genetic liability is stillunaccounted for. Leading theories of the pathophysiology ofschizophrenia include the glutamate and dopamine pathways. Glutamate isthe major excitatory neurotransmitter in the nervous system.

A number of drugs have been approved to treat schizophrenia. However,patient response to treatment remains highly variable, and thediscontinuation rate with antipsychotic treatment is high. No singleantipsychotic agent offers optimal effect for every patient withschizophrenia. Few data are available to guide clinicians and patientsin the selection of the most appropriate medication, and in theimprovement of treatment specificity for an individual patient.

Iloperidone(1-[4-[3-[4-(6-flouro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone)is an atypical antipsychotic disclosed in U.S. Pat. No. RE39198.Metabolites of iloperidone, e.g., P88 (also referred to as P-88-8891 or1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanol),are also useful in the present invention. See, e.g., InternationalPatent Application Publication No. WO03020707, which is incorporatedherein by reference. Other iloperidone metabolites include:1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone;1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-2-hydroxyethanone;4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α-methylbenzenemethanol;4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl-2-hydroxy-5-methoxy-α-methylbenzenemethanol;1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-hydroxy-5-methoxyphenyl]ethanone;and1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2,5-dihydroxyphenyl]ethanone.See U.S. Pat. No. 5,364,866, and International Patent ApplicationPublication Nos. WO9309276 and WO9511680.

Previous studies have investigated associations between iloperidoneefficacy and polymorphisms in genes and gene regions including CFTR,NPAS3, XKR4, TNR, GRIA4, GFRA2, and NUDT9P1. These associations aredescribed in, e.g., U.S. Pat. Nos. 9,328,387, 9,458,507, and 9,080,214.Additionally, associations between CYP2D6 and KCNQ1 genotypes andchanges in QT interval following the administration of iloperidone aredescribed in U.S. Pat. Nos. 8,586,610, 9,138,432, 8,999,638, and9,157,121. Such findings relating to the efficacy of iloperidone aid inselection of the most optimal drug and dosage regimen for a particularpatient. This in turn aids in safe and effective treatment of psychoticsymptoms, diseases, and disorders, with less trial and error.

SUMMARY OF THE INVENTION

In a first aspect of the invention, an improvement is provided in amethod consisting of administering to a schizophrenia patient an amountof an active pharmaceutical ingredient (API), effective to treat saidpatient's schizophrenia. In various embodiments, the activepharmaceutical ingredient (API) may be an antipsychotic agent, which mayfurther be a typical antipsychotic agent such as, e.g., chlorpromazine,fluphenazine, haloperidol, perphenazine, thioridazine, or thiothixene,or may be an atypical antipsychotic agent such as, e.g., aripiprazole,asenapine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone,quetiapine, risperidone, or ziprasidone. In other embodiments, the APImay be an mGluR5 agonist. The improvement comprises selecting thepatient for treatment with the API based upon a determination that saidpatient's gene sequence includes a mutation in PPEF2. In variousembodiments, the mutation in PPEF2 is a loss of function mutation. Moreparticularly, the mutation may be a missense mutation such as R86H, or astopgain mutation such as PPEF2:NM_006239:exon3:c.G135A:p.W45X. Incertain embodiments, the atypical antipsychotic agent may beiloperidone, a metabolite of iloperidone, or a pharmaceuticallyacceptable salt of iloperidone or the metabolite thereof, and inparticular, the amount of iloperidone may be between 12 mg/day and 24mg/day, depending on factors including but not limited to severity ofsymptoms, patent genotype at various loci relevant to the disease ormetabolism of the drug, and other considerations.

In a second aspect of the invention, a method is provided for treating aschizophrenia patient with an active pharmaceutical ingredient (API),comprising: identifying the patient's genotype at the PPEF2 locus; andif the patient carries a mutation in PPEF2, then internallyadministering the API to the patient at a dose of 12-24 mg/day dependingon factors including but not limited to those described above. The stepof identifying may further comprise: obtaining or having obtained abiological sample from the patient; and performing or having performed agenotyping assay on the biological sample to determine the patient'sPPEF2 genotype. In various embodiments, the mutation in PPEF2 is a lossof function mutation. More particularly, the mutation may be a missensemutation such as R86H, or a stopgain mutation such asPPEF2:NM_006239:exon3:c.G135A:p.W45X. In various embodiments, the APImay be an antipsychotic agent, which may further be a typicalantipsychotic agent such as, e.g., chlorpromazine, fluphenazine,haloperidol, perphenazine, thioridazine, or thiothixene, or may be anatypical antipsychotic agent such as, e.g., aripiprazole, asenapine,clozapine, iloperidone, lurasidone, olanzapine, paliperidone,quetiapine, risperidone, or ziprasidone. In other embodiments, the APImay be an mGluR5 agonist. In certain embodiments, the atypicalantipsychotic agent may be iloperidone, a metabolite of iloperidone, ora pharmaceutically acceptable salt of iloperidone or the metabolitethereof, and in particular, the amount of iloperidone may be between 12mg/day and 24 mg/day, depending on factors including but not limited toseverity of symptoms, patent genotype at various loci relevant to thedisease or metabolism of the drug, and other considerations.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the pedigree (“pedigree 1”) of a family included inthe study described in Example 1.

FIG. 2 illustrates results of the study described in Example 1.

FIG. 3 illustrates an immunoblot showing influence of PPEF2 onFLAG-tagged metabotropic glutamate receptor subtype 5 (mGluR5) oncotransfection in the presence of the 3,5 dihydroxyphenylglycine agonistin HEK293 cells, courtesy of Timms, et al. (2013).

DETAILED DESCRIPTION

Various embodiments of the invention provide improved methods fortreating psychotic diseases, disorders, and symptoms thereof using anactive pharmaceutical ingredient (API) that may be an antipsychoticagent or an mGluR5 agonist, selecting patients for such treatment on thebasis of identifying those whose gene sequences include genetic variantsidentified herein, and predicting the likelihood that a particularpatient will respond significantly and favorably to treatment. Invarious embodiments, the psychotic disease being treated may beschizophrenia.

A method is provided in which an API administered to a patient sufferingfrom schizophrenia in an amount effective to treat said patient'sschizophrenia, in which the patient is selected on the basis of genotypeat the PPEF2 locus. In particular embodiments, the patient be selectedon the basis of having a stopgain mutation in PPEF2, and the mutationmay more particularly be the LOF PPEF2:NM_006239:exon3:c.G135A:p.W45Xvariant. In other embodiments, the patient may be selected for treatmenton the basis of having a missense variant (R86H) in PPEF2. In variousembodiments, the API may be an antipsychotic agent, which may further bea typical antipsychotic agent such as, e.g., chlorpromazine,fluphenazine, haloperidol, perphenazine, thioridazine, or thiothixene,or may be an atypical antipsychotic agent such as, e.g., aripiprazole,asenapine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone,quetiapine, risperidone, or ziprasidone. In other embodiments, the APImay be an mGluR5 agonist. In certain embodiments, the atypicalantipsychotic agent may be iloperidone, a metabolite of iloperidone, ora pharmaceutically acceptable salt of iloperidone or the metabolitethereof, and in particular, the amount of iloperidone may be between 12mg/day and 24 mg/day, depending on factors including but not limited toseverity of symptoms, patent genotype at various loci relevant to thedisease or metabolism of the drug, and other considerations.

A method is further provided for treating schizophrenia in a patientwith an API as defined above, including identifying whether thepatient's gene sequence includes a variant in PPEF2. The identifyingstep may include a number of different methods of identification. In oneaspect, identifying a genotype may include performing a genotyping assayon a biological sample collected from the patient to be treated. Thebiological sample may include, e.g., blood, serum, saliva, urine, et al.as is known in the art. The performance of such an assay may includesteps such as, e.g., extracting genomic DNA or mRNA from the biologicalsample, and sequencing DNA derived from the extracted genomic DNA orfrom the extracted mRNA, including amplifying a gene region in theextracted genomic DNA or mRNA to prepare a DNA sample enriched with DNAfrom the relevant gene region. The DNA sample may then be hybridized tonucleic acid probes to determine whether the patient has a genotype ofinterest.

In some embodiments, identifying a genotype may include reviewing apatient's medical history, result report, or other document containingthe result of a previously-performed assay or genetic test. In stillfurther aspects, the identifying may include causing or requesting anassay to be performed by another individual, or causing or requestingthe review of the patient's medical history, result report, or otherdocument containing the result of a previously-performed assay orgenetic test.

In any event, the method includes identifying the patient's PPEF2genotype, for example, determining whether the patient carries, e.g., amissense variant such as R86H, or a stopgain mutation such as the LOFvariant, PPEF2:NM_006239:exon3:c.G135A:p.W45X. If the patient's genotypeincludes such a variant, then the patient may be predisposed toschizophrenia, and in particular may be predisposed to early onset ofschizophrenia. In this instance, the patient may particularly benefitfrom treatment with the API, which may be, e.g., a typical antipsychoticagent such as chlorpromazine, fluphenazine, haloperidol, perphenazine,thioridazine, or thiothixene, an atypical antipsychotic agent such asaripiprazole, asenapine, clozapine, iloperidone, lurasidone, olanzapine,paliperidone, quetiapine, risperidone, or ziprasidone, or an mGluR5agonist. In certain embodiments, the atypical antipsychotic agent may beiloperidone, a metabolite of iloperidone, or a pharmaceuticallyacceptable salt of iloperidone or the metabolite thereof, and inparticular, the amount of iloperidone may be between 12 mg/day and 24mg/day, depending on factors including but not limited to severity ofsymptoms, patent genotype at various loci relevant to the disease ormetabolism of the drug, and other considerations. The method may includeinternally administering the API, for example iloperidone, to thepatient at a dose of between 12 mg/day and 24 mg/day, e.g., 12 mg/day,14 mg/day, 16 mg/day, 18 mg/day, 20 mg/day, 22 mg/day, or 24 mg/day. Invarious embodiments, enhanced monitoring may be indicated where thepatient receives relatively larger doses of iloperidone, e.g., 20mg/day, 22, mg/day, or 24 mg/day. In cases in which the patient has agenotype that does not include one of the foregoing variants, thepatient may not be genetically predisposed to schizophrenia, or moreparticularly may not be predisposed to early onset schizophrenia. Inthis instance, the patient's psychotic symptoms may be treated using adifferent treatment regimen, which may include administration of adifferent drug.

The foregoing methods collectively aid physicians in prospectivelyidentifying patients who are at increased risk of developingschizophrenia, particularly early onset schizophrenia, and willparticularly benefit from treatment with an API such as, e.g.,iloperidone. The ability to identify patients who are likely to benefitfrom treatment prior to commencement of treatment itself provides ameaningful benefit to patients and practitioners as it reduces theamount of trial and error that a patient must endure before identifyingan effective treatment regimen to gain and maintain control of psychoticsymptoms.

An effective amount of an API such as, e.g., iloperidone or an activemetabolite thereof may be administered to a subject animal (typically ahuman but other animals, e.g., farm animals, pets and racing animals,can also be treated) by a number of routes. An effective amount is anamount that during the course of therapy will have a preventive orameliorative effect on a psychotic disorder, such as schizophrenia, or asymptom thereof, or of bipolar disorder. An effective amount mayquantitatively vary depending upon, for example, the patient, theseverity of the disorder or symptom being treated, and the route ofadministration.

It will be understood that the dosing protocol including the amount ofAPI, for example iloperidone, a metabolite of iloperidone, or apharmaceutically acceptable salt of iloperidone or the metabolitethereof actually administered will be determined by a physician in thelight of the relevant circumstances including, for example, thecondition to be treated, the chosen route of administration, the age,weight, and response of the individual patient, and the severity of thepatient's symptoms. Patients should be monitored for possible adverseevents.

For therapeutic use, the API, for example, iloperidone, a metabolite ofiloperidone, or a pharmaceutically acceptable salt of iloperidone or themetabolite thereof will normally be administered as a pharmaceuticalcomposition as the (or an) essential active ingredient at least one suchcompound in association with a solid or liquid pharmaceuticallyacceptable carrier and, optionally, with pharmaceutically acceptableadjuvants and excipients employing standard and conventional techniques.

Pharmaceutical compositions useful in the practice of this inventioninclude suitable dosage forms for oral, parenteral (includingsubcutaneous, intramuscular, intradermal and intravenous), transdermal,bronchial or nasal administration. Thus, if a solid carrier is used, thepreparation may be tableted, placed in a hard gelatin capsule in powderor pellet form, or in the form of a troche or lozenge. The solid carriermay contain conventional excipients such as binding agents, fillers,tableting lubricants, disintegrants, wetting agents and the like. Thetablet may, if desired, be film coated by conventional techniques. If aliquid carrier is employed, the preparation may be in the form of asyrup, emulsion, soft gelatin capsule, sterile vehicle for injection, anaqueous or non-aqueous liquid suspension, or may be a dry product forreconstitution with water or other suitable vehicle before use. Liquidpreparations may contain conventional additives such as suspendingagents, emulsifying agents, wetting agents, non-aqueous vehicle(including edible oils), preservatives, as well as flavoring and/orcoloring agents. For parenteral administration, a vehicle normally willcomprise sterile water, at least in large part, although salinesolutions, glucose solutions and like may be utilized. Injectablesuspensions also may be used, in which case conventional suspendingagents may be employed. Conventional preservatives, buffering agents andthe like also may be added to the parenteral dosage forms. Thepharmaceutical compositions may be prepared by conventional techniquesappropriate to the desired preparation containing appropriate amounts ofAPI, for example, iloperidone or an active metabolite thereof. See, forexample, Remington's Pharmaceutical Sciences, Mack Publishing Company,Easton, Pa., 17th edition, 1985.

In making pharmaceutical compositions for use in the invention, theactive ingredient(s) will usually be mixed with a carrier, or diluted bya carrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, semi-solid or liquid material which acts asa vehicle, excipient or medium for the active ingredient. Thus, thecomposition can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing forexample up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions andsterile packaged powders.

Some examples of suitable carriers and diluents include lactose,dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calciumphosphate, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water,syrup, methyl cellulose, methyl- and propylhydroxybenzoates, talc,magnesium stearate and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents or flavoring agents. Thecompositions of the invention may be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient.

The compositions are preferably formulated in a unit dosage form. Theterm “unit dosage form” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired prophylactic or therapeutic effect over the courseof a treatment period, in association with the required pharmaceuticalcarrier.

Iloperidone and its active metabolites can also be formulated in acontrolled release form, e.g., delayed, sustained, or pulsatile release.Various formulations and methods of administering iloperidone and/or itsderivatives have been described. For example, U.S. Pat. Nos. 8,227,488;8,293,765; and 8,614,232 describe an injectable depot formulationcomprising iloperidone crystals; and microencapsulated depotformulations of iloperidone and a polyglycolide polylactide glucose starpolymer are described in U.S. Pat. Nos. 7,767,230 and 8,815,293.

EXAMPLE 1

An in-patient, open label, sequential dose escalation study is conductedto evaluate the safety, tolerability, and pharmacokinetics ofiloperidone long active injectable (LAI). Up to 27 study participantsenroll, each of whom may be male or female, is aged 18 to 65 years(inclusive), is diagnosed with schizophrenia according to DSM-V criteriafor at least one year, and is symptomatically stable. The studyparticipants include a family with three (3) affected male individualsthat developed schizophrenia at 9, 11, and 17 years of age respectively(FIG. 1 ), indicating a strong genetic predisposition for schizophreniawithin the family.

A blood sample is drawn from each participant at the screening visit,and whole genome sequencing (WGS) is performed in order to detectgenetic factors predisposing individuals to early onset schizophrenia.WGS is performed on DNA samples obtained from study participants usingIllumina HiSeq X instruments, enabling sequencing of up to 18,000 30×human whole genomes. Whole genome data are processed on New York GenomeCenter (NYGC) automated pipelines. Paired-end 150 bp reads are alignedto the GRCh37 human reference (BWA-MEM v0.7.8) and processed with GATKbest practices workflow (GATK v.3.4.0). Sequencing results are annotatedusing ANNOVAR software. Normal population allelic frequencies areextracted from Exome Aggregation Consortium (ExAC) and GenomeAggregation Database (gnomAD). LOF fold change analysis is conducted vs.gnomAD frequencies. Finally, WGS Loss of Function analysis of themutation landscape and functional analysis of PPEF2 are conducted.

Results

Whole genome sequencing in XX subjects with schizophrenia identify anovel rare stopgain mutation in PPEF2 (Protein Phosphatase With EF-HandDomain 2) in a family with 3 affected individuals. The LOFPPEF2:NM_006239:exon3:c.G135A:p.W45X has a minor allele frequency (MAF)of 2.83E-05 in ExAC and has a combined annotation dependent deletion(CADD) score of 37 (˜ 1/30000 carrier). Population allelic frequenciesare shown in Table 1.

TABLE 1 Population Frequencies Allele Allele Number of Allele Populationcount number homozygotes frequency African 3 16240 0 0.0001847 Other 16124 0 0.0001633 Latino 0 34570 0 0.000 Ashkenazi Jewish 0 10078 0 0.000East Asian 0 18384 0 0.000 European (Finnish) 0 21646 0 0.000 European(non- 0 113624 0 0.000 Finnish) South Asian 0 30616 0 0.000 Male 3135854 0 0.00002208 Female 1 115428 0 0.000008663 Total 4 251282 00.00001592

Discussion

PPEF2 encodes a neuronally expressed protein phosphatase that bindscalmodulin. PPEF2 appears to be involved in the N-methyl-D-aspartatereceptor network by affecting the levels of certain brain nerve cellsignaling mediators. Specifically, HEK293 cells transfected with PPEF2demonstrate increased levels of mGluR5 in the presence of an mGluR5agonist, suggesting that disturbance of PPEF2 could lower mGluR5membrane levels.

A missense substitution was previously reported for a single family withmultiple affected individuals with schizophrenia. Intriguingly, allaffected individuals in a pedigree (A. E. Timms, et al., “Support forthe N-methyl-D-aspartate receptor hypofunction hypothesis ofschizophrenia from exome sequencing in multiplex family,” JAMAPsychiatry. vol. 70, no. 6(Print), pp. 582-90 (June 2013)) share amissense variant (R86H) in PPEF2. Given that mGluR5 and PPEF2 both bindcalmodulin, they investigated whether PPEF2 expression influences mGluR5levels. The observation that HEK293 cells transfected with PPEF2demonstrate increased levels of mGluR5 in the presence of the mGluR5agonist suggests that disturbance of PPEF2 could lower mGluR5 membranelevels. This mutation supports the N-Methyl-D-Aspartate ReceptorHypofunction Hypothesis of Schizophrenia from WGS data.

Whole genome sequencing delineates a novel deleterious variant in PPEF2as a likely genetic risk factor for schizophrenia in a family with three(3) affected male individuals. This finding provides useful informationfor characterizing a rare mutation that may predispose individuals todeveloping schizophrenia and help elucidate the pathway leading to thisdisorder as well as potential new therapeutic targets. Additionalgenomic screens that stratify patients based on the affected geneticpathways may better guide the most effective treatments.

The foregoing description of various aspects of the invention has beenpresented for purposes of illustration and description. It is notintended to be exhaustive or to limit the invention to the precise formdisclosed, and modifications and variations are possible. Suchmodifications and variations that may be apparent to a person skilled inthe art are intended to be included within the scope of the invention asdefined by the accompanying claims.

We claim:
 1. In a method consisting of administering to a schizophreniapatient an amount of an active pharmaceutical ingredient (API) effectiveto treat said patient's schizophrenia, the improvement comprising:selecting said patient for treatment based upon a determination thatsaid patient's gene sequence includes a mutation in PPEF2.
 2. Theimprovement of claim 1, wherein the API comprises: an atypicalantipsychotic agent selected from a group consisting of: aripiprazole,asenapine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone,quetiapine, risperidone, and ziprasidone; a typical antipsychotic agentselected from a group consisting of: haloperidol, chlorpromazine,fluphenazine, perphenazine, thioridazine, and thiothixene; or an mGluR5agonist.
 3. The improvement of claim 1, wherein the API is selected froma group consisting of: iloperidone, a metabolite of iloperidone, or apharmaceutically acceptable salt of iloperidone or the metabolitethereof.
 4. The improvement of claim 3, wherein the treatment comprisesadministering a long-acting injectable (LAI) formulation containing theAPI.
 5. The improvement of claim 4, wherein the administering furthercomprises intramuscularly injecting the LAI formulation.
 6. Theimprovement of claim 3, wherein the treatment comprises orallyadministering a solid immediate release formulation comprising the APIand a pharmaceutically acceptable carrier.
 7. The improvement of claim6, further comprising orally administering the API in an amount of 12mg/day to 24 mg/day.
 8. The improvement of claim 1, in which themutation in PPEF2 is selected from a loss of function mutation, amissense mutation, and a stopgain mutation.
 9. The improvement of claim8, in which the missense mutation is R86H.
 10. The improvement of claim8, wherein the stopgain mutation isPPEF2:NM_006239:exon3:c.G135A:p.W45X.
 11. A method for treating aschizophrenia patient, comprising: identifying the patient's genotype atthe PPEF2 locus; and if the patient has a genotype including a mutationin PPEF2, then internally administering an active pharmaceuticalingredient (API) to the patient.
 12. The method of claim 11, wherein theAPI comprises: an atypical antipsychotic agent selected from a groupconsisting of: aripiprazole, asenapine, clozapine, iloperidone,lurasidone, olanzapine, paliperidone, quetiapine, risperidone, andziprasidone; a typical antipsychotic agent selected from a groupconsisting of: haloperidol, chlorpromazine, fluphenazine, perphenazine,thioridazine, and thiothixene; or an mGluR5 agonist.
 13. The method ofclaim 11, wherein the API is selected from a group consisting of:iloperidone, a metabolite of iloperidone, and a pharmaceuticallyacceptable salt of iloperidone or the metabolite thereof.
 14. The methodof claim 13, wherein internally administering the API to the patientfurther comprises administering a long-acting injectable (LAI)formulation containing the API and at least one pharmaceuticallyacceptable carrier.
 15. The method of claim 14, wherein theadministering further comprises intramuscularly injecting.
 16. Themethod of claim 13, wherein the internally administering furthercomprises orally administering a solid immediate release form comprisingthe API and at least one pharmaceutically acceptable carrier, andwherein the API is orally administered in an amount of 12 mg/day to 24mg/day.
 17. The method of claim 11, in which the mutation in PPEF2 isselected from a loss of function mutation, a missense mutation, and astopgain mutation.
 18. The method of claim 17, in which the missensemutation is R86H.
 19. The method of claim 17, wherein the stopgainmutation is PPEF2:NM_006239:exon3:c.G135A:p.W45X.
 20. The methodaccording to claim 11, wherein the step of identifying comprises:obtaining or having obtained a biological sample from the patient; andperforming or having performed a genotyping assay on the biologicalsample to determine the patient's PPEF2 genotype.